Genetic and Epigenetic Regulation of Human lincRNA Gene Expression
Genetic and Epigenetic Regulation of Human lincRNA Gene Expression
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DOI：
10.1016/j.ajhg.2013.10.022
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发表时间：
2013-12-05
影响因子：
9.8
通讯作者：
Antonarakis, Stylianos E.
中科院分区：
文献类型：
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作者：
Popadin, Konstantin;Gutierrez-Arcelus, Maria;Antonarakis, Stylianos E.
大的基因间非编码RNA（lincRNA）的功能仍然很差。我们通过使用来自195个无关欧洲个体的三种细胞类型分析了GenCord集合中人类lincRNA表达的遗传和表观遗传调节。我们检测了大量的顺式表达数量性状基因座（cis-eQTL），证明lincRNA表达的遗传调控不依赖于相邻蛋白质编码基因的调控。lincRNA的cis-eQTLs相对多于相同外显子数的同等表达的蛋白质编码基因。lincRNA cis-eQTL位于更靠近转录起始位点（TSS）的位置，并且它们的效应大小高于蛋白质编码基因的cis-eQTL，表明lincRNA表达水平比蛋白质编码基因的表达水平受到更少的限制。此外，lincRNA cis-eQTL可以影响附近蛋白质编码基因的表达水平，因此可以被认为是增强子活性的QTL。增强子标记中表达的lincRNA启动子的富集为lincRNA参与顺式转录调节提供了另一个论据。通过研究lincRNA的表观遗传调控，我们观察到DNA甲基化和基因表达（表达数量性状甲基化[eQTM]）之间的正相关和负相关，正如预期的那样，并发现DNA甲基化在基因调控中的被动和主动作用的景观与蛋白质编码基因相似。然而，lincRNA eQTM比蛋白质编码基因eQTM更靠近TSS。lincRNA和蛋白质编码基因在遗传和表观遗传调控方面的这些相似性和差异有助于阐明lincRNA的潜在功能。
Large intergenic noncoding RNAs (lincRNAs) are still poorly functionally characterized. We analyzed the genetic and epigenetic regulation of human lincRNA expression in the GenCord collection by using three cell types from 195 unrelated European individuals. We detected a considerable number of cis expression quantitative trait loci (cis-eQTLs) and demonstrated that the genetic regulation of lincRNA expression is independent of the regulation of neighboring protein-coding genes. lincRNAs have relatively more cis-eQTLs than do equally expressed protein-coding genes with the same exon number. lincRNA cis-eQTLs are located closer to transcription start sites (TSSs) and their effect sizes are higher than cis-eQTLs found for protein-coding genes, suggesting that lincRNA expression levels are less constrained than that of protein-coding genes. Additionally, lincRNA cis-eQTLs can influence the expression level of nearby protein-coding genes and thus could be considered as QTLs for enhancer activity. Enrichment of expressed lincRNA promoters in enhancer marks provides an additional argument for the involvement of lincRNAs in the regulation of transcription in cis. By investigating the epigenetic regulation of lincRNAs, we observed both positive and negative correlations between DNA methylation and gene expression (expression quantitative trait methylation [eQTMs]), as expected, and found that the landscapes of passive and active roles of DNA methylation in gene regulation are similar to protein-coding genes. However, lincRNA eQTMs are located closer to TSSs than are protein-coding gene eQTMs. These similarities and differences in genetic and epigenetic regulation between lincRNAs and protein-coding genes contribute to the elucidation of potential functions of lincRNAs.